Age-specific incidence of cancer: Phases, transitions, and biological implications.
The observation that the age-specific incidence curve of many carcinomas is approximately linear on a double logarithmic plot has led to much speculation regarding the number and nature of the critical events involved in carcinogenesis. By a consideration of colorectal and pancreatic cancers in the Surveillance Epidemiology and End Results (SEER) registry we show that the log-log model provides a poor description of the data, and that a much better description is provided by a multistage model that predicts two basic phases in the age-specific incidence curves, a first exponential phase until the age of approximately 60 followed by a linear phase after that age. These two phases in the incidence curve reflect two phases in the process of carcinogenesis. Paradoxically, the early-exponential phase reflects events between the formation (initiation) of premalignant clones in a tissue and the clinical detection of a malignant tumor, whereas the linear phase reflects events leading to initiated cells that give rise to premalignant lesions because of abrogated growth/differentiation control. This model is consistent with Knudson's idea that renewal tissue, such as the colon, is converted into growing tissue before malignant transformation. The linear phase of the age-specific incidence curve represents this conversion, which is the result of recessive inactivation of a gatekeeper gene, such as the APC gene in the colon and the CDKN2A gene in the pancreas.
Meza
Rafael
R
Program in Biostatistics and Biomathematics and Program in Computational Biology, Fred Hutchinson Cancer Research Center 1100 Fairview Avenue North, Seattle, WA 98109-1024, USA. rmeza@fhcrc.org
Jeon
Jihyoun
J
Moolgavkar
Suresh H
SH
Luebeck
E Georg
EG
D017677:Age Distribution; D001695:Biology; D005260:Female; D006801:Humans; D008297:Male; D009369:Neoplasms / Q000453:epidemiology* / Q000473:pathology*; D012727:Sex Characteristics; D013997:Time Factors